Tag: Lung Cancer: Non-Small Cell

Tremelimumab in Combination with Durvalumab and Chemotherapy in Metastatic Non Small Cell Lung Cancer: The Phase III POSEIDON Study

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the T cells of the immune system. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response.

IMFINZI® (Durvalumab) is a human immunoglobulin G1 monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics, and unleashes the T cells. IMJUDO® (Tremelimumab) is a human immunoglobulin G2 monoclonal antibody that targets and blocks the activity of CTLA-4, enhancing binding of CD80 and CD86 to CD28. This complimentary mechanisms of action broadens clinical activity, potentially overcoming primary resistance to PD-(L)1 blockade by enabling novel T-cell responses. The concurrent addition of chemotherapy to checkpoint inhibitors causes tumor cell death and release of neoantigens, which increases immune priming, important for early disease control.

POSEIDON is a global, randomized, open-label, three-arm, Phase III study, which evaluated the efficacy of Tremelimumab plus Durvalumab along with chemotherapy, and Durvalumab along with chemotherapy, compared to chemotherapy alone, in first-line treatment of metastatic NSCLC. In this trial, 1013 patients (N=1013) with EGFR/ALK wild-type metastatic NSCLC were randomly assigned (1:1:1) to receive either Tremelimumab 75 mg IV plus Durvalumab 1,500 mg IV along with chemotherapy for up to four 21-day cycles, followed by Durvalumab 1500 mg IV once every 4 weeks until disease progression, with one additional Tremelimumab dose after chemotherapy at week 16 (fifth dose), Durvalumab 1500 mg IV plus chemotherapy for up to four 21-day cycles, followed by Durvalumab 1500 mg IV once every 4 weeks until disease progression, or chemotherapy alone for up to six 21-day cycles. Chemotherapy options for treatment groups included Carboplatin plus nab-Paclitaxel regardless of histology, Cisplatin or Carboplatin plus Gemcitabine for patients with squamous histology, and Cisplatin or Carboplatin plus Pemetrexed for patients with nonsquamous histology. Patients with nonsquamous histology who received Pemetrexed-Platinum doublet could receive Pemetrexed maintenance therapy if eligible. Patients continued treatment until progressive disease or unacceptable toxicity. Patients were stratified by PD-L1 expression (50% or more versus less than 50%), disease Stage (IVA versus IVB), and histology (squamous versus nonsquamous). The median age was 64 yrs, 63% had nonsquamous histology, and approximately a third of the patients had PD-L1 expression less than 1%. The treatment groups were well balanced. The Primary end points were Progression Free Survival (PFS) and Overall Survival (OS) for the Durvalumab plus chemotherapy group, compared to the chemotherapy alone group. Key Secondary end points were PFS and OS for Tremelimumab plus Durvalumab along with chemotherapy, compared to chemotherapy alone.

The coPrimary end point of PFS benefit with Durvalumab plus chemotherapy compared to chemotherapy alone was met (HR=0.74; P=0.0009), and the median PFS was 5.5 versus 4.8 months respectively and the 12-month PFS rates were 24.4% versus 13.1%. However, OS did not reach statistical significance (HR=0.86; P=0.075). When Secondary end points were formally evaluated, Tremelimumab plus Durvalumab and platinum-based chemotherapy demonstrated a statistically significant and clinically meaningful improvement in OS compared to chemotherapy alone (HR=0.77; P=0.003). The median OS was 14 months versus 11.7 months respectively and 2 year OS was 32.9% versus 22.1% respectively. The median PFS was 6.2 months and 4.8 months in the treatment arms, respectively (HR=0.72; P=0.0003) and the 1-year PFS rate was 26.6% and 13.1% respectively. Treatment benefit was seen across all PD-L1 subgroups, particularly in tumors with PD-L1 expression of 50% or more. Patients with tumor PD-L1 expression less than 1% appeared to gain improved survival benefit from the addition of Tremelimumab to Durvalumab and chemotherapy.

Based on this study, the FDA approved Tremelimumab in combination with Durvalumab and platinum-based chemotherapy for adult patients with metastatic NSCLC, with no sensitizing EGFR mutation or ALK genomic tumor aberrations.

It was concluded that Durvalumab plus chemotherapy significantly improved Progression Free Survival when compared to chemotherapy alone. A limited course of Tremelimumab added to Durvalumab and chemotherapy significantly improved Overall Survival and Progression Free Survival when compared to chemotherapy, and the clinical benefit extended to patients who had tumor PD-L1 expression less than 1%.

Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non–Small-Cell Lung Cancer: The Phase III POSEIDON Study. Johnson ML, Cho BC, Luft A, et al. DOI: 10.1200/JCO.22.01737 Journal of Clinical Oncology 41, no. 6 (February 20, 2023) 1176-1179.

Five Year Outcomes with KEYTRUDA® Plus Chemotherapy in Metastatic Nonsquamous Non Small Cell Lung Cancer

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

KEYTRUDA® is a fully humanized, immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. High level of Programmed Death-Ligand 1 (PD-L1) expression is defined as membranous PD-L1 expression on at least 50% of the tumor cells, regardless of the staining intensity. It is estimated that based on observations from previous studies, approximately 25% of the patients with advanced NSCLC have a high level of PD-L1 expression and high level of PD-L1 expression has been associated with significantly increased response rates to KEYTRUDA®.

KEYNOTE-189 is a double-blind, Phase III trial in which 616 patients with untreated Stage IV non-squamous NSCLC, without sensitizing EGFR or ALK mutations, were randomly assigned in a 2:1 ratio to receive treatment with four cycles of KEYTRUDA®/Pemetrexed/Carboplatin (N=410) or placebo plus the same chemotherapy (N=206). Patients then received either KEYTRUDA® 200 mg or saline placebo, both administered IV every 3 weeks for up to 35 cycles. All the patients received four cycles of the investigator’s choice of Cisplatin 75 mg/m2 IV or Carboplatin AUC 5 along with Pemetrexed 500 mg/m2, all administered IV every 3 weeks, followed by maintenance Pemetrexed 500 mg/m2 every 3 weeks. Patients in the placebo combination group were allowed to crossover to KEYTRUDA® monotherapy upon disease progression. Patients with symptomatic brain metastasis were excluded and patients were stratified according to PD-L1 expression (Tumor Proportion Score, 1% or more versus less than 1%), choice of platinum-based drug (Cisplatin versus Carboplatin), and smoking history. Both treatment groups were well balanced and about 17% had brain metastasis and one-third were untreated. A PD-L1 Tumor Proportion Score of 1% or more was reported in 63% of the patients, Carboplatin was the preferred platinum-based drug in 72% of the patients, and 88% of the patients were current or former smokers. The co-Primary end points were Overall Survival (OS) and Progression Free Survival (PFS). Secondary end points included Objective Response Rate (ORR) and Duration of Response (DOR) and Safety. Exploratory end points included PFS2 (time from random assignment to second/subsequent progressive disease on next-line treatment or death from any cause).

In the initial report from the trial, after a median follow-up of 10.5 months, the median PFS was 8.8 months in the KEYTRUDA® combination group and 4.9 months in the placebo combination group (HR=0.52; P<0.001) and the median OS was Not Reached with KEYTRUDA® combination and was 11.3 months in the placebo combination group (HR=0.49; P<0.001).

In this updated analysis, the researchers presented 5-year outcomes from the Phase III KEYNOTE-189 study. The median time from randomization to data cutoff (in March 2022) was 64.6 months. There was continued benefit in the Progression Free Survival and Overall Survival in the KEYTRUDA® group compared to the control group (HR=0.50 versus HR=0.60, respectively). The 5-year Progression Free Survival rates were 7.5% versus 0.6% and 5-year Overall Survival rates were 19.4% versus 11.3% respectively. The Objective Response Rate in the KEYTRUDA® group was 48.3% versus 19.9% in the control group, and the median Duration of Response was 12.7 and 7.1 months, respectively. Similar trends were observed across the PD-L1 subgroups analyzed. Among the 57 patients assigned to KEYTRUDA® combination and completed 35 cycles of KEYTRUDA®, the Objective Response Rate was 86% and the estimated Overall Survival rate 3 years after completion of 35 cycles (approximately 5 years from random assignment) was 71.9%. Sustained improvements in Overall Survival were observed in the KEYTRUDA® combination group, despite a crossover rate of 57% of patients from placebo plus chemotherapy to subsequent anti-PD1 therapy, further supporting the use of KEYTRUDA® plus chemotherapy as first-line treatment.

It was concluded that KEYTRUDA® in combination with Pemetrexed and Platinum chemotherapy continued to demonstrate prolonged survival and durable antitumor activity, compared to chemotherapy alone, regardless of PD-L1 expression. The authors added that these data continue to support the combination of first-line KEYTRUDA® plus a Platinum and Pemetrexed as a standard of care, in patients with previously untreated metastatic nonsquamous NSCLC, without EGFR/ALK alterations.

Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non–Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. Garassino MC, Gadgeel S, Speranza G, et al. DOI: 10.1200/JCO.22.01989 Journal of Clinical Oncology. Published online February 21, 2023.

STK11 Mutation

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Both STK11 (also called LKB1) and KEAP1 mutation occur in about 17% of Non Small Cell Lung Cancer (adenocarcinomas), respectively, and correlates with poor outcome with immune checkpoint inhibitors or immune checkpoint inhibitors plus chemotherapy. KRAS is frequently comutated with STK11, KEAP1, and TP53 and these subgroups confer different prognostic outcomes. Within the KRAS mutated population, STK11 and/or KEAP1 mutations are associated with inferior Overall Survival and Progression Free Survival across treatments, compared with STK11-wild type and/or KEAP1-wild type. It appears that anti PD-1/anti-PD-L1 immune checkpoint inhibitors in combination with anti-angiogenic agent and chemotherapy is an efficacious first-line treatment in metastatic NSCLC subgroups with KRAS mutations co-occurring with STK11 and/or KEAP1 or TP53 mutations and/or high PD-L1 expression.

Lobar or Sublobar Resection for Peripheral Stage IA Non Small Cell Lung Cancer

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Low Dose CT (LDCT) screening for lung cancer resulted in a 20% reduction in mortality In the National Lung Screening Trial (NLST). The USPSTF expanded the criteria for lung cancer screening in 2021 and recommended annual screening with Low-Dose CT for adults aged 50-80 years who have a 20 pack-year smoking history and currently smoke or have quit within the past 15 years. Approximately 15% of patients present with early stage (T1-2 N0) disease, and these numbers are likely to increase with the more rigorous implementation of lung cancer screening programs.

Surgical resection is the primary treatment for approximately 30% of patients with NSCLC who present with early Stage (I–IIIA) disease. Pneumonectomy is rarely performed due to unacceptably high mortality rate. Lobectomy has been the standard of surgical care for patients with clinical T1N0 NSCLC since the mid 1990s. This was based on the results of a randomized trial comparing Lobectomy with Sublobar resection in patients with clinical T1N0 NSCLC. In this trial, the frequency of local recurrence was three times higher with Sublobar resection compared with Lobectomy, and lung cancer-related mortality was 50% higher with Sublobar resection.Types-of-Lung-Resection

Sublobar resection includes Wedge resection and Segmentectomy. In Wedge resection, the lung tumor is removed with a surrounding margin of normal lung tissue, and is not an anatomical resection. Segmentectomy, unlike Wedge resection, is an anatomical resection that usually includes one or more pulmonary parenchymal segments with the dissection of intraparenchymal and hilar lymph nodes. Advances in imaging as well as staging by means of mediastinoscopy, and routine intraoperative lymphadenectomy has enabled the identification of small, peripheral NSCLCs for which Sublobar resection was potentially appropriate. Sublobar resection was considered a “compromise operation” in selected high risk patients with early stage lung cancer. With the approval of lung cancer screening in high risk individuals and subsequent detection of small tumors, Sublobar resections have been on the rise and may be the preferred surgical option, even in good-risk patients, in many institutions. Sublobar resection preserves pulmonary function and leaves open more treatment options for NSCLC patients, who remain at high risk for metachronous primary NSCLC, following curative intervention for their first NSCLC.

With the implementation of CT-based lung cancer screening recently, lung cancers are likely detected at a very early stage (T1a-bN0; 2 cm or less, node negative tumors). Further, Adenocarcinoma now is the most frequent histologic subtype of lung cancer and present as peripherally located tumors. Advances in preoperative staging such as endobronchial ultrasonography, have improved patient selection for treatment. Majority of surgical resections are now performed by means of video or robotic-assisted thoracic surgery. This has improved postoperative outcomes, with significant reduction in perioperative morbidity, mortality and median length of hospital stay after either Sublobar resection or Lobectomy.

The authors in this study reported the results of a randomized international trial comparing Sublobar resection (wedge resection or segmentectomy) with Lobectomy, in patients with clinical Stage IA NSCLC, with a tumor size of 2 cm or less. Cancer and Leukemia Group B (CALGB) 140503 was a multicenter, international, randomized, noninferiority, Phase III trial, involving patients with NSCLC clinically staged as T1aN0. In this study, a total of 697 patients, after intraoperative confirmation of node-negative disease, were randomly assigned to undergo either Sublobar resection (N=340) or Lobar resection (N=357). Of the 340 patients assigned to Sublobar resection, 201 (59.1%) underwent wedge resection and 129 (37.9%) underwent an anatomical segmental resection. Wedge resection was allowed in the current trial as it is the most frequently practiced method of Sublobar resection in North America and Europe and its inclusion would make the trial more representative of a “real world” setting. The median patient age was 68 years. Approximately 50% of patients had tumor size 1.0-1.5 cm, 40% had tumor size 1.5-2.0 cm, and two thirds of the patients had Adenocarcinoma histology. Over 90% of the patients were current or former smokers. The Primary end point was Disease-Free Survival (DFS), defined as the time between randomization and disease recurrence or death from any cause. Secondary end points included Overall Survival (OS), locoregional and systemic recurrence, and pulmonary functions.

After a median follow up of 7 years, Sublobar resection was noninferior to Lobar resection for DFS (HR for disease recurrence or death=1.01). The 5-year DFS was 63.6% after Sublobar resection and 64.1% after Lobar resection. The Overall Survival after Sublobar resection was similar to that after Lobar resection (HR for death, 0.95). The 5-year OS was 80.3% after Sublobar resection and 78.9% after Lobar resection. No substantial difference was seen between the two groups in the incidence of locoregional or distant recurrence. At 6 months postoperatively, pulmonary functions favored the Sublobar resection group.

It was concluded that Sublobar resection by either anatomical segmentectomy or wedge resection, for patients with peripheral NSCLC with a tumor size of 2 cm or less and pathologically confirmed node-negative disease in the hilar and mediastinal lymph nodes, was non inferior to Lobectomy, with respect to Disease Free Survival and with similar Overall Survival, and is an effective management approach for this subgroup of patients with NSCLC.

Lobar or Sublobar Resection for Peripheral Stage IA Non–Small-Cell Lung Cancer. Altorki N, Wang X, Kozono D, et al. N Engl J Med 2023; 388:489-498

FDA Approves Adjuvant KEYTRUDA® in NSCLC Irrespective of PD-L1 Expression

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SUMMARY: The FDA on January 26, 2023, approved KEYTRUDA® (Pembrolizumab) for adjuvant treatment following resection and platinum-based chemotherapy for Stage IB (T2a ≥4 cm), II, or IIIA Non-Small Cell Lung Cancer (NSCLC). Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

The 5-year survival rate for patients diagnosed with lung cancer in the US is about 25%, which is a significant improvement over the past 5 years, in part due to earlier detection from lung cancer screening, reduction in smoking, advances in diagnostic and surgical procedures, as well as the introduction of new therapies. However, the 5-year survival rate remains significantly lower among communities of color at 20%. Early detection and screening remain an important unmet need, as 44% of lung cancer cases are not found until they are advanced. In the US, only 5.8% of those individuals at high risk were screened in 2021.

Surgical resection is the primary treatment for approximately 30% of patients with NSCLC who present with early Stage (I–IIIA) disease. These patients are often treated with platinum-based adjuvant chemotherapy to decrease the risk of recurrence. Nonetheless, 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response.

KEYNOTE-091/EORTC-1416-LCG/ETOP-8-15 – PEARLS trial is a multicenter, randomized, triple-blind, placebo-controlled Phase III trial, which compared the efficacy of KEYTRUDA® with placebo, among patients with resected NSCLC. In this study, 1,177 patients with completely resected Stage IB (T2a ≥4 cm), II, or IIIA NSCLC with negative margins, and with tumor tissue available for PD-L1 testing were included. Systematic complete or lobe-specific mediastinal lymph node dissection was recommended. In the least, the subcarinal and 1 lobe-specific lymph node must have been examined. Eligible patients had not received neoadjuvant radiotherapy or chemotherapy, had ECOG PS of 0-1, and adjuvant chemotherapy for up to four cycles was optional. Adjuvant chemotherapy could be considered for those with Stage IB disease and was strongly recommended for those with Stage II and IIIA disease. Patients were randomized (1:1) to receive KEYTRUDA® 200 mg or placebo IV every three weeks and treatment was continued until disease recurrence, unacceptable toxicity, or up to 1 year. Both treatment groups were well balanced. The median patient age was 65 years, majority of patients (68%) were male, approximately 65% of patients had nonsquamous histology, 56% of patients had Stage II disease and 86% of patients had received adjuvant platinum-based chemotherapy following complete resection. Stratification factors included disease stage, receipt of adjuvant chemotherapy, PD-L1 Tumor Proportion Score and geographic region of the world. The median duration of exposure to KEYTRUDA® was 11.7 months and 68% of patients in the KEYTRUDA® group were exposed to KEYTRUDA® for at least 6 months. The major efficacy outcome measure was investigator-assessed Disease-Free Survival (DFS). An additional efficacy outcome was Overall Survival (OS).

The trial met its Primary endpoint, demonstrating a statistically significant improvement in DFS in the overall population. In patients who received adjuvant platinum-based chemotherapy following surgical resection, KEYTRUDA® reduced the risk of disease recurrence or death by 27% (HR=0.73) versus placebo, regardless of PD-L1 expression. For patients who received adjuvant chemotherapy, median DFS regardless of PD-L1 expression was 58.7 months in the KEYTRUDA® group versus 34.9 months in the placebo group. In an exploratory subgroup analysis of the 167 patients who did not receive adjuvant chemotherapy, the DFS Hazard Ratio was 1.25. Overall survival Data were not mature.

It was concluded that these data support the benefit of KEYTRUDA® as a new adjuvant immunotherapy treatment option, for early-stage NSCLC following complete resection, and if indicated, adjuvant chemotherapy, regardless of PD-L1 expression.

EORTC-1416-LCG/ETOP 8-15 – PEARLS/KEYNOTE-091 study of pembrolizumab versus placebo for completely resected early-stage non-small cell lung cancer (NSCLC): Outcomes in subgroups related to surgery, disease burden, and adjuvant chemotherapy use.O’Brien M, Paz-Ares L, Jha N, et al. DOI: 10.1200/JCO.2022.40.16_suppl.8512 Journal of Clinical Oncology 40, no. 16_suppl (June 01, 2022) 8512-8512.Published online June 02, 2022.

EGFR Exon 20 Insertion Mutations – These Are NOT Your Common EGFR Mutations

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Written By: David M. Waterhouse, MD, MPH & Anita Koshy, MD
This promotional educational activity is brought to you by Janssen Biotech, Inc., and is not certified for continuing medical education.
Dr. Waterhouse is a paid consultant writing on behalf of Janssen Biotech, Inc., and must present this information in compliance with FDA requirements applicable to Janssen Biotech, Inc.

It is estimated that approximately 237,000 people in the US will be diagnosed with lung cancer in 2022. Despite advancements in standard-of-care treatments for lung cancer, this disease remains the leading cause of cancer death in both males and females.1 Nonetheless, the burgeoning number of targeted therapies for some types of lung cancer, particularly non-small cell lung cancer (NSCLC), have allowed for improvements in mortality and survival.2 As of 2022, there are ~20 targeted therapies for ~9 actionable driver mutations in stage IV NSCLC.3,4 In order to determine optimal targeted therapies, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend comprehensive biomarker testing, like next-generation sequencing (NGS), for all eligible patients at diagnosis of advanced NSCLC.5

Common EGFR Mutations (Exon 19 deletion and Exon 21 [L858R] mutations)

Epidermal growth factor receptor (EGFR) is a potent oncogene commonly altered in NSCLC, and EGFR driver mutations may be found in as many as 28% of metastatic NSCLC patients.6 Tyrosine kinase inhibitors (TKIs) directed against EGFR were among the first molecular targeted agents used for treatment of advanced NSCLC.7 Initial studies of EGFR TKIs showed that patient characteristics associated with EGFR mutations, such as non-smoking status, female gender, East Asian origin, and adenocarcinoma histology suggested a greater benefit from EGFR TKIs compared with first-line chemotherapy.8 Later studies identified gene mutations that could target the kinase domain of EGFR and predicted response to such inhibitors. The variable deletions of at least 3 amino acid residues in exon 19, as well as the single point mutation leucine-858 to arginine (L858R) in exon 21, are often referred to as “common” activating EGFR mutations and represent the vast majority (90%) of all observed EGFR kinase domain mutations in NSCLC.8 (Figure 1)EGFR-Mutations

EGFR Exon 20 Insertion Mutations

Exon 20 insertion mutations are the third most prevalent type of activating EGFR mutations in NSCLC and are associated with a poor prognosis.9-11 These mutations are also enriched in women, non-smokers, Asian populations, and those with adenocarcinoma. Exon 20 insertion mutations, however, lack the key structural features that confer sensitivity of L858R and exon19 deletion mutations to first-and second-generation EGFR inhibitors. In-frame base pair insertions in exon 20 result in activation of EGFR, but, unlike the common activating EGFR mutations, they are associated with reduced affinity to most clinically available EGFR TKIs indicated for common EGFR mutations. Data are limited and variable, but multiple studies found that patients with EGFR exon 20 insertion mutations had an overall response rate of 0% to 8.7% when treated with first-, second-, or third-generation EGFR TKIs.12-16 (Figure 2)

Median-PFS-First-Second-Generation_TKI

*These data were taken from a retrospective observational study.16
†Common mutations include L858R, L861Q, and exon 19 deletions.16
‡These data were taken from multiple sources: a cohort study, a prospective post hoc analysis of phase 2 and phase 3 trials, a single-center retrospective analysis, and a systematic literature review and meta-analysis.12-14
HR, hazard ratio; ORR, overall response rate; PFS, progression-free survival.

Study results also demonstrate limited efficacy of immuno-oncology (IO) monotherapy in this patient population compared to patients with wild-type EGFR. In a retrospective study using real-world data, patients with EGFR exon 20 insertion mutation-positive NSCLC were associated with a 58% increased risk of shorter time to next-line therapy after first-line IO monotherapy compared to patients with wild-type NSCLC.17

The NCCN Guidelines® do not recommend most TKIs or IO monotherapy for treating patients with mNSCLC and EGFR exon 20 insertion mutations in the first- or second-line setting. Instead, the Guidelines recommend platinum-based chemotherapy as the standard first-line treatment for NSCLC with EGFR exon 20 insertion mutations.5§

§Exceptions include p.A763_Y764insFQEA and p.A763_Y764insLQEA.5

EGFR Testing

The NCCN Guidelines recommend comprehensive biomarker testing, like NGS, prior to the initiation of first-line therapy, if clinically feasible.5 Despite that recommendation, rates of broad biomarker testing remain low, according to real-world evidence.18,19 In a retrospective observational chart review study among 3,474 patients with advanced NSCLC receiving first-line therapy in the US Oncology Network, the EGFR testing rate was found to be 70%, but comprehensive NGS testing was completed in only 42% of patients.20 Failure to order comprehensive NGS testing is particularly problematic when it comes to identifying EGFR exon 20 insertions. There are over 100 unique EGFR exon 20 insertion variants, and polymerase chain reaction (PCR) testing can miss approximately 50% of the insertions identified by NGS.21 (Figure 3)

EGFR-Mutations-Foundation-Medicine

||Analysis from mutation profiles of 36,465 lung adenocarcinomas from Foundation Medicine (Cambridge, MA) FoundationInsights database, which is a database of 315,688 patient genomic profiles across 150 cancer types.
¶Commercially available qPCR methods were Roche cobas® EGFR mutation test v2 and Qiagen therascreen EGFR RGQ PCR kit.

Another notable issue is the accurate application of NGS data to clinical care. In multiple retrospective, observational cohort studies, approximately 17% to 24% of treatment-naive and 14% to 22% of second-line patients with EGFR exon 20 insertions received EGFR TKIs.11,17,22** Studies also found that approximately 7% to 40% of treatment-naive and 26% to 41% of second-line patients received IO monotherapy.17,22,23 These therapies (ie, most TKIs indicated for common mutations†† and IO monotherapies) are not recommended for first- or second-line therapy for EGFR exon 20 insertion mutations.5

**EGFR TKIs included first-, second- and third-generations.
††Exceptions include p.A763_Y764insFQEA and p.A763_Y764insLQEA.

Current Treatment Strategies for Patients With Exon 20 Insertion Mutations
Chemotherapy with a platinum doublet remains the recommended treatment option for the first-line treatment of patients with an EGFR exon 20 insertion mutation.5 When many of these patients progress, subsequent treatment options are needed. The NCCN Guidelines recommend amivantamab-vmjw or mobocertinib as subsequent therapy options for patients with EGFR exon 20 insertion mutations who have progressed on or after initial systemic therapy.5

Conclusion:

  • Advances made in the treatment of NSCLC have improved patient mortality and survival,2 and these advancements are due in part to the discovery of actionable mutations, like common EGFR mutations, and targeted therapies3,4,7,8
  • Multiple studies have found, however, that patients with EGFR exon 20 insertion mutations had a poor overall response when treated with first-, second-, or third-generation EGFR TKIs,11-15,17 and that IO monotherapies provide little benefit as a first-line treatment in patients with EGFR mutations, including exon 20 insertions17
  • The NCCN Guidelines recommend:
    • Testing eligible patients with mNSCLC for targetable genetic alterations to both identify potentially appropriate targeted therapies and avoid therapies unlikely to provide clinical benefit5
    • Treating patients who harbor a common EGFR mutation (exon 19 deletion and exon 21 [L858R] mutations) with an EGFR TKI in the first line of treatment, whereas those with an EGFR exon 20 insertion mutation are best treated with a regimen containing a platinum doublet5
    • Amivantamab-vmjw or mobocertinib as subsequent therapy options for patients with EGFR+ mNSCLC with exon 20 insertion mutations who have progressed on or after initial systemic therapy per the NCCN Guidelines5

References
1. National Cancer Institute. Cancer stat facts: common cancer sites. Accessed September 30, 2022. https://seer.cancer.gov/statfacts/html/common.html
2. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021.CA Cancer J Clin. 2021;71:7-33.
3. Benjamin DJ, Haslam A, Gill J, Prasad V. Targeted therapy in lung cancer: Are we closing the gap in years of life lost? Cancer Med. 2022;11(18):3417-3424.
4. Targeted Therapy in Metastatic Non–Small Cell Lung Cancer: Recent Updates and Controversies. Angel Qin. ASCO Daily News. Published January 19, 2022. Accessed November 14, 2022. https://dailynews.ascopubs.org/do/10.1200/ADN.22.200810/
5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.6.2022. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed December 2, 2022. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in anyway.
6. Jordan EJ, Kim HR, Arcila ME, et al. Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov. 2017;7(6):596-609.
7. Luo SY, Lam DC. Oncogenic driver mutations in lung cancer. Transl Respir Med. 2013;1(1):6.
8. Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene. 2009;28 (Suppl 1):S24-S31.
9. Arcila ME, Nafa K, Chaft JE, et al. EGFR exon20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther. 2013;12(2):220-229.
10. Leal JL, Alexander M, Itchins M, et al. EGFR exon 20 insertion mutations: clinicopathological characteristics and treatment outcomes in advanced non-small cell lung cancer. Clin Lung Cancer. 2021;22(6):e859-e869.
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KRAZATI® (Adagrasib)

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The FDA on December 12, 2022, granted accelerated approval to KRAZATI® (Adagrasib), a RAS GTPase family inhibitor, for adult patients with KRAS G12C-mutated locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy. KRAZATI® is a product of Mirati Therapeutics, Inc.

IMJUDO® (Tremelimumab)

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The FDA on November 10, 2022, approved IMJUDO® (Tremelimumab) in combination with IMFINZI® (Durvalumab) and platinum-based chemotherapy for adult patients with metastatic Non-Small Cell Lung Cancer (NSCLC) with no sensitizing Epidermal Growth Factor Receptor (EGFR) mutation or Anaplastic Lymphoma Kinase (ALK) genomic tumor aberrations. Both IMJUDO® and IMFINZI® are products of AstraZeneca Pharmaceuticals.